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Similar bronchodilation withformoterol delivered by Aerolizer

or Turbuhaler

J Lötvall MD PhD1, A Mellén MD1, P Arvidsson MD1,M Palmqvist MD PhD1, P Radielovic MD2, J Kottakis MD3, P Pfister MD2

1Department of Respiratory Medicine and Allergology, Institute of Heart and Lung Diseases,Göteborg University, Sahlgrenska University Hospital,

Gothenburg, Sweden; 2Clinical Development & Regulatory Affairs, Novartis Pharma, Basel,Switzerland; 3Medical School, University of Crete, Greece

412 Can Respir J Vol 6 No 5 September/October 1999

ORIGINAL ARTICLE

Correspondence: Dr Jan Lötvall, The Lung Pharmacology Group, Department of Respiratory Medicine and Allergology, GöteborgUniversity, Sahlgrenska University Hospital, Bruna Stråket 11, S-413 45 Göteborg, Sweden. Telephone +011-46-31-342967,fax +011-46-413290, e-mail [email protected]

J Lötvall, A Mellén, P Arvidsson, et al. Similar broncho-dilation with formoterol delivered by Aerolizer or Tur-buhaler. Can Respir J 1999;6(5):412-416.

BACKGROUND: In many countries, two dry powderformulations of inhaled formoterol are available for clinicaluse; one uses a single-dose device (Foradil, Aerolizer), andthe other uses a multiple-dose device (Oxis, Turbuhaler).OBJECTIVES: To study the bronchodilating effect of for-moterol 12 �g when delivered via the Aerolizer and Turbu-haler devices over 12 h.STUDY DESIGN: Randomized, double-blind, placebocontrolled crossover study. Forced expiratory volume in onesecond (FEV1) was monitored during a 12 h period.PATIENTS: Nineteen nonsmoking asthma patients were in-cluded in the trial on the basis of reversibility of symptoms inresponse to inhaled salbutamol (either 200 or 400 �g givencumulatively; minimum reversibility 15%).RESULTS: There were no significant differences betweenthe two dry powder devices regarding the change from base-line of FEV1 over 12 h, the area under the curve of FEV1 over12 h or the maximum value of FEV1. The improvement inFEV1 with formoterol 12 �g versus placebo was highly sig-nificant for both devices.CONCLUSIONS: Formoterol is similarly effective whenused as a dry powder when given by either Aerolizer or theTurbuhaler.

Key Words: Asthma; Beta2-agonist; Bronchodilators; Inhalationtherapy

Bronchodilatation similaire avec du formotéroldélivré par Aerolizer ou Turbuhaler

HISTORIQUE : Dans de nombreux pays, deux formulations depoudre sèche de formotérol pour inhalation sont disponiblespour un usage clinique ; l’une utilise un dispositif à dose unique(Foradil, Aerolizer) et l’autre, un dispositif à doses multiples(Oxis, Turbuhaler).OBJECTIFS : Étudier l’effet bronchodilatateur du formotérol12 µg/dose par inhalation au moyen de Aerolizer et de Turbuha-ler, sur une période de 12 h.MODÈLE DE L’ÉTUDE : Étude croisée, randomisée, à dou-ble insu et contrôlée par placebo. Le volume expiratoiremaximum/seconde (VEMS) a été monitoré pendant une périodede 12 h.PATIENTS : Dix neuf patients asthmatiques non-fumeurs ontété inclus dans l’essai sur la base d’une réversibilité de leurssymptômes en réponse à l’inhalation de salbutamol (soit 200 ou400 µg administrés de façon cumulative ; réversibilité minimalede 15 %).RÉSULTATS : On n’a observé aucune différence significativeentre les deux dispositifs de poudre sèche en ce qui concerne lechangement à partir de la valeur de référence du VEMS sur unepériode de 12 h, l’aire sous la courbe du VEMS pendant 12 h oula valeur maximale du VEMS. L’amélioration du VEMS aprèsl’inhalation de formotérol 12 µg/dose par rapport au placeboétait nettement significative pour les deux dispositifs.CONCLUSIONS : Le formotérol en poudre sèche démontreune efficacité équivalente qu’il soit administré par Aerolizer oupar Turbuhaler.

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Formoterol fumarate (Foradil, Novartis Pharmaceuticals,Canada Inc, Dorval, Quebec) is a potent and selectivebeta2-adrenergic receptor agonist that is highly effective inrelaxing bronchial smooth muscle (1-9). Formoterol drypowder has a rapid onset of action, as well as a duration of ac-tion of at least 12 h. In single-dose trials in adults, 12 �g and24 �g of formoterol aerosol and dry powder provide a rapidonset of action, within 1 to 3 mins (4-8). Also, dose-responsestudies with formoterol aerosol and dry powder demonstratethat a substantial portion of the bronchodilating effect ismaintained at 12 h after inhalation (2,9). Improvements inlung function and control of asthma symptoms with for-moterol inhalation are maintained during up to five years oftreatment without evidence of a reduced bronchodilator re-sponse or worsening of asthma control (10-13).

All available powder inhalers are driven by the inspiratoryflow achieved by the patient, and the dose deposited in theairways is dependent on several factors, including the inspi-ratory effort produced by the patient, the inbuilt resistance ofthe inhaler and the resulting inspiratory flow. Dry powder in-halers may have slightly different deposition characteristics,depending on the profile of aerosol delivered. Bronchodila-tors have traditionally been delivered via propellant drivenpressurized metered dose inhaler (pMDI). However, totaldrug dose delivered with dry powder devices appears to besimilar to that delivered with traditional pMDI (14-18).

Two dry powder formulations of inhaled formoterol havebecome available for clinical use. One uses a single-dose de-vice (previously known as the Inhaled Single Formulationdevise, Aerolizer, Novartis Pharma, Basel, Switzer-land/Italseber Farmaceutici, Italy) and the other a multiple-dose device (Oxis/formoterol/Turbuhaler, Astra Draco,Lund, Sweden). Both these devices use lactose as a carriersubstance, and both are breath actuated.

The aim of the present study was to compare the clinicalefficacy of 12 �g formoterol when delivered by either Aerol-izer or Turbuhaler to adult patients with reversible airflowlimitation.

MATERIALS, PATIENTS AND METHODSThe single-dose delivery device (Aerolizer) has a low in-

ternal resistance, and a gelatine capsule containing 12 �g for-moterol is loaded in the capsule chamber before use. Whenthe patient inspires through the device, the capsule is liftedout of the capsule chamber into the inhalation chamber whereit rotates to release powder (formoterol and lactose) into theairstream. The multiple-dose delivery device (Turbuhaler)has a higher internal resistance and contains 60 doses of ei-ther 6 �g or 12 �g formoterol. This device is activated byturning a knob at the bottom of the device, and one dose of 6�g or 12 �g is released when the patient inspires through thedevice. The turbulence in the mouthpiece generates the parti-

Can Respir J Vol 6 No 5 September/October 1999 413

Formoterol given by two different dry powder inhalers

TABLE 1Patient characteristics and lung function data (forced expiratory volume in 1 s [FEV1]) of 19 patients testingbronchodilation with formoterol delivered by Aerolizer or Turbuhaler

Patient number Sex Age (years) Height (cm) Weight (kg) FEV1 basal Predicted FEV1 FEV1 (% predicted)

1 Male 67 176 90 1.81 3.16 57

2 Female 72 162 66 1.28 2.02 63

3 Male 65 183 83 2.29 3.52 65

4 Female 52 166 66 1.90 2.68 71

5 Female 68 168 119 1.38 2.31 60

6 Female 50 168 72 1.27 2.81 45

7 Female 50 165 92 1.81 2.69 67

8 Male 72 171 88 1.34 2.80 48

9 Male 60 163 67 2.62 2.81 93

10 Female 51 175 88 2.29 3.06 75

11* Male 37 184 85 2.79 4.38 64

12 Male 71 178 82 1.56 3.13 50

13 Male 73 178 94 1.98 3.08 64

19 Female 52 165 93 2.41 2.64 91

20 Male 49 186 78 3.93 4.12 95

21 Female 67 168 56 2.48 2.39 104

22 Male 30 179 72 3.39 4.39 77

23 Male 25 183 88 3.90 4.68 83

24 F 44 167 63 2.56 2.92 88

MEAN 55 173 81 2.26 3.13 72

SEM 3 0.18 0.17 4

*The patient discontinued treatment after visit 3

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cles delivered to the patient. The dose delivered to the lungsand the distribution of the aerosol in the lung may thus differbetween the two devices. Because formoterol is a potentbeta2-adrenergic receptor agonist, even small differencesmay be clinically relevant to the patient in terms of efficacyand safety.Patients: Nineteen nonsmoking patients (mean age 55 years,range 25 to 73 years; nine females, 10 males) with moderateasthma (defined according to the American Thoracic Societycriteria) requiring daily treatment with inhaled bronchodila-tators and corticosteroids were included in the trial. One pa-tient attended only three of four visits. Patient data arepresented in Table 1. In all, the diagnosis of chronic reversi-ble obstructive airways disease (with forced expiratory vol-ume in 1 s [FEV1] more than 40% of predicted) had beenpreviously established. After written consent was obtained,lung function (FEV1) was measured. Mean FEV1 at inclu-sion was 2.26 L, and mean FEV1 per cent predicted was 72%.A reversibilty of at least 15% of FEV1 had to be documented15 mins after 200 �g or 400 �g salbutamol powder was deliv-ered by Diskhaler (Glaxo Wellcome Ltd, Ware, UnitedKingdom). The reason for this reversibility test was to ensureresponse to a bronchodilating drug in the participating pa-tients. Eight of the patients used salbutamol as concomitantmedication, six generic salbutamol, five terbutaline and foursalmeterol (Serevent, Glaxo Wellcome Inc, Mississauga,Ontario). Only one used ipratropium bromide (Atrovent,Boehringher Ingelheim Ltd, Laval, Quebec), one formoterol(Oxis Turbuhaler) and one Theo-dur (Astra Draco, Lund,Sweden). All patients were on inhaled glucocorticoids.

The study was approved by the Ethics Committee at Göte-borg University, Gothenburg, Sweden, and was performed inaccordance with the Declaration of Helsinki and conductedaccording to the guidelines for Good Clinical Practice.Study design: Patients were randomly assigned to one of the

sequences of the three trial treatments by a computer gener-ated list at visit 2. The order of inhalation from either deviceon each study day was randomized among patients. All treat-ments were administered between 07:00 and 10:00 on visits2, 3 and 4, and were supervised by a technician or nurse.Between the treatment visits, a washout period of at leastthree days (72 h), and up to 10 days, was scheduled. Pa-tients continued to use their usual asthma medication dur-ing the study.Methods: FEV1 was measured by dry spirometer (Vitalo-graph Ltd, Buckingham, United Kingdom). Just before theadministration of formoterol or placebo via Aerolizer or Tur-buhaler devices, at 3, 7, 15, 30 and 45 mins, and 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11 and 12 h after medication the best of threeforced expirations were accepted and registered in the casereport form. Only one measurement was performed at 3, 7,15 and 30 mins to save time.Data analysis: The primary objective of this study was tocompare the efficacy of a single dose of 12 �g formoterol viathe Aerolizer device and the Turbuhaler device versus pla-cebo. The primary variable for this comparison was the 12 haverage FEV1 (area under the FEV1 curve versus time, di-vided by 12 h). Secondary objectives of the study were tocompare the maximum value of FEV1 (irrespective of timepoint that this is achieved), FEV1 at all time points, and per-centage change from predose baseline at all time points. Pa-tients who received treatment and had efficacy measure-ments for at least two treatment days were analyzed. For theprimary variables, confirmatory analyses were performed ata significance level of 5% (two-sided). No adjustment formultiple testing was performed. The treatment contrastswere tested in the following order: formoterol Aerolizer ver-sus placebo, formoterol Turbuhaler versus placebo, and for-moterol Aerolizer versus formoterol Turbuhaler. All FEV1data were log-transformed before statistical analysis.

ANCOVA, including log-transformed baseline FEV1 as acovariate, was performed to test for differences among treat-ments. The results (eg, confidence interval) were antiloggedto be expressed as ratios.

RESULTSThere were no differences in baseline FEV1 among the

different study days. The time-course of FEV1 over 12 h onthe different study days is shown in Figure 1. The time courseof the mean change in FEV1 following the single dose of for-moterol 12 �g by both the Aerolizer and Turbuhaler was sig-nificantly greater than placebo at each time point. Thedifferences between Aerolizer and Turbuhaler were not sig-nificant at any time point.

The maximal FEV1 was 2.27±0.03 L on the placebo day,and 2.47±0.035 L and 2.51±0.04 L on the Aerolizer and Tur-buhaler days, respectively (P

Aerolizer and Turbuhaler days, respectively (P

pharmacological properties and therapeutic potential in reversibleobstructive airways disease. Drugs 1991;42:115-37.

13. Bartow RA, Brogden RN. Formoterol. An update of itspharmacological properties and therapeutic efficacy in the managementof asthma. Drugs 1998;55:303-22.

14. Rabe FK, Jörres R, Nowak D, Behr N, Magnussen H. Comparison ofthe effects of salmeterol and formoterol on airway tone andresponsiveness over 24 hours in bronchial asthma. Am Rev Respir Dis1993;147:1436-41.

15. Moore RH, Khan A, Dickey BF. Long-acting inhaled beta2-agonists inasthma therapy. Chest 1998;113:1095-108.

16. Selroos O. The pharmacological and clinical properties of Oxis(formoterol) Turbuhaler. Allergy 1998;53(42 Suppl):14-9.

17. Thomson NC, Angus R, Quebe-Fehling E, Brambilla R. Efficacy and

tolerability of formoterol in elderly patients with reversible obstructiveairways disease. Respir Med 1998;92:562-7.

18. Selroos O, Pietinalho A, Riska H. Delivery devices for inhaled asthmamedication. Clinical implications of differences of effectiveness.Clin Immunother 1996;6:273-99.

19. Brown PH, Ning ACWS, Greening AP, McLean A, Crompton GK.Peak inspiratory flow through Turbuhaler in acute asthma. Eur Respir J1995;8:1940-1.

20. Steffensen I, Faurschou P, Riska H, Rostrup J, Wegener T.Inhaled formoterol dry powder in the treatment of patients withreversible obstructive airways disease. A 3-month, placebo-controlledcomparison of the efficacy and safety of formoterol and salbutamol,followed by a 12-month trial with formoterol. Allergy1995;50:657-63.

416 Can Respir J Vol 6 No 5 September/October 1999

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